The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art, or relevant, to the presently described or claimed invention, or that any publication or document that is specifically or implicitly identified is prior art or a reference that may be used in evaluating patentability. All documents and other information referred to in this patent are incorporated herein by reference in their entirety.
Over the past two decades, much research effort has been directed towards the development of medical devices and machines that are used in a wide variety of clinical settings to repair, maintain, or enhance vital physiological functions of a subject mammal. For example, devices such as catheters, prosthetic heart valves, pacemakers, pulse generators, cardiac defibrillators, arteriovenous shunts, and stents are used extensively in the treatment of cardiac and other diseases. Other examples of medical devices, including screws, anchors, plates, staples, tacks, joints and similar devices, for example, are used in orthopedic surgery. These implantable medical devices are made from a wide variety of materials, including, for example, metals, plastics, and various polymeric materials. Other orthopedic devices include implants, such as implants for hip, shoulder, elbow and knee replacements and surgeries, or craniomaxillofacial reconstruction, and implant coatings, as well devices used in arthroscopic and laproscopic procedures, including burrs, suture-passing instruments, arthroscopic shavers. Other examples of medical devices include ocular devices, such as implants, including intraocular lenses and glaucoma shunts. Still other devices include gastrointestinal implants. Other examples of medical devices include devices for endoscopy, hysteroscopy, cytoscopy, bronchoscopy, etc.
When medical devices, for example, implantable medical devices, are brought into contact with a subject, natural bodily processes can result in inflammation, swelling, hypercellularity or other aberrant cellular disposition, growth and/or proliferation, and/or tissue damage. For example, platelets may attach to the medical device which can result in further complications at the site of use or implantation such as, for example, thrombosis, leukocyte attachment, and/or neutrophil and/or macrophage migration that lead to inflammation and/or aberrant cellular growth. An example of such a process resulting from the contacting of a medical device with a subject is provided by the use of a catheter or stent, which can result in tissue damage and/or restenosis. Restenosis, the reclosure of a peripheral or coronary artery following trauma to that artery generally caused by efforts to open a stenosed or occluded portion of the artery, and resulting trauma may be caused by, for example, balloon dilation, ablation, atherectomy or laser treatment of the artery. For example, balloon arterial injury reportedly results in endothelial denudation and subsequent regrowth of dysfunctional endothelium that may contribute to the local smooth muscle cell proliferation and extracellular matrix production that result in reocclusion of the arterial lumen. Restenosis has been reported to occur in as many as 50% of patients undergoing such angioplasty procedures. Restenosis is believed to be a natural healing process in reaction to the injury of the arterior wall caused by such angioplasty procedures. The healing process begins with the thrombotic mechanism at the site of the injury. The final steps of the healing process can be intimal hyperplasia, the uncontrolled migration and proliferation of medial smooth muscle cells, combined with their extracellular matrix production, until the artery is again stenosed or occluded.
In humans and other mammals wound injury triggers an organized complex cascade of cellular and biochemical events that will in most cases result in a healed wound. An ideally healed wound is one that restores normal anatomical structure, function, and appearance at the cellular, tissue, organ, and organism levels. Wound healing, whether initiated by trauma, microbes or foreign materials, proceeds via a complex process encompassing a number of overlapping phases, including inflammation, epithelialization, angiogenesis and matrix deposition. Normally, these processes lead to a mature wound and a certain degree of scar formation. Although inflammation and repair mostly occur along a prescribed course, the sensitivity of the process is dependent on the balance of a variety of wound healing modulating factors, including for example, a network of regulatory cytokines and growth factors.
Despite advances in the understanding of the principles underlying the wound healing process, there remains a significant unmet need in suitable therapeutic options for wound care, including delayed or compromised wound healing of wounds such as chronic wounds, as well as swelling, inflammation, epithelialization rates and scarring associated with these and other wounds, including acute and subacute wounds.
Gap junctions are cell membrane structures that facilitate direct cell-cell communication. A gap junction channel is formed of two connexons (hemichannels), each composed of six connexin subunits. Each hexameric connexon docks with a connexon in the opposing membrane to form a single gap junction. Gap junction channels are reported to be found throughout the body. Tissue such as the corneal epithelium, for example, has six to eight cell layers, yet is reported to expresses different gap junction channels in different layers with connexin 43 in the basal layer and connexin 26 from the basal to middle wing cell layers. In general, connexins are a family of proteins, commonly named according to their molecular weight or classified on a phylogenetic basis into alpha, beta, and gamma subclasses. At least 20 human and 19 murine isoforms have been identified. Different tissues and cell types are reported to have characteristic patterns of connexin protein expression and tissues such as cornea have been shown to alter connexin protein expression pattern following injury or transplantation (Qui, C. et al., (2003) Current Biology, 13:1967-1703; Brander et al., (2004), J. Invest Dermatol. 122:1310-20).
It has been reported that, abnormal connexin function may be linked to certain disease states (e.g. heart diseases) (A. C. de Carvalho, et al., J Cardiovasc Electrophysiol 1994, 5 686). In certain connexin proteins, alterations in the turnover and trafficking properties may be induced by the addition exogenous agents which may affect the level of gap junctional intercellular communication (Darrow, B. J., et al. (1995). Circ Res 76: 381; Lin R, et al. (2001) J Cell Biol 154(4):815). Antisense technology has been reported for the modulation of the expression for genes implicated in viral, fungal and metabolic diseases. See, e.g., U.S. Pat. No. 5,166,195, (oligonucleotide inhibitors of HIV), U.S. Pat. No. 5,004,810 (oligomers for hybridizing to herpes simplex virus Vmw65 mRNA and inhibiting replication). See also U.S. Pat. No. 7,098,190 to Becker et al. (formulations comprising antisense nucleotides to connexins). See also Becker and Green PCT/US06/04131 (“Anti-connexin compounds and uses thereof”).
There is a need for medical devices that will aid in ameliorating tissue damage and/or enhancing tissue repair and/or limiting or inhibiting complications associated with using or implanting medical devices in a subject, such as for example, inflammation, restenosis and so on. It would be desirable to provide a medical device that aids in prevention, amelioration or treatment of damaged tissue and/or inflammation, and/or the enhancement of tissue repair, as well as swelling, hypercellularity or other aberrant cellular disposition, growth and/or proliferation, and/or tissue damage. Such devices, methods of manufacture, and uses thereof, are provided herein.